Prediction of the responsiveness to treatment with erythropoiesis-stimulating factors: a prospective clinical study in patients with solid tumors

OBJECTIVE: Treatment with erythropoiesis-stimulating factors (ESFs) can ameliorate anemia associated with cancer and chemotherapy. However, half of anemic cancer patients do not respond even to high doses. To determine factors that are predictive of a treatment response, a multicenter, prospective study was performed. PATIENTS AND METHODS: Investigated factors were baseline erythropoietin, reticulocytes and soluble transferrin receptor (sTfR) after 2 weeks, and reticulocytes and hemoglobin after 4 weeks. Anemic patients with solid tumors received 150 microg/week of darbepoetin concomitantly with chemotherapy. The dose was doubled if hemoglobin did not increase by >1 g/dl after 4 weeks. Patients were considered responders if hemoglobin increased by >or=2 g/dl or reached a level >or=12 g/dl within 8-12 weeks. RESULTS: In total, 196 patients were enrolled; 61% of the intention-to-treat (ITT) and 68% of the per-protocol population were responders. In the ITT population, the hemoglobin increase after 4 weeks indicated an 11-fold higher chance of response (odds ratio, 11.0; 95% confidence interval [CI], 5.1-23.6; sensitivity, 88%; specificity, 60%). In a multiple logistic regression model including all factors, the area under the receiver operating characteristic curve was 0.78 (95% CI, 0.71-0.84). The combination of sTfR after 2 weeks and hemoglobin after 4 weeks was as predictive as the combination of all five tested factors. CONCLUSION: So far, an early hemoglobin increase remains the single most predictive factor for response to ESF treatment. In contrast to anemic patients with lymphoproliferative malignancies, serum erythropoietin had little predictive value in patients with solid tumors.     

Exclusion/confirmation of Ataxia-telangiectasia via cell-cycle testing

Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder with increased radiosensitivity and cancer susceptibility. The responsible gene (ATM) consists of 66 exons and a coding region of 9171 bp which precludes direct sequencing as a screening assay for confirmation or exclusion of the clinical suspicion of AT. Peripheral blood mononuclear cells of 330 patients referred for the exclusion of AT were exposed to ionizing radiation (IR) and incubated for 72 h in the presence of phytohemagglutinin. Using bivariate BrdU-Hoechst/ethidium bromide flowcytometry, the following cell cycle parameters were ascertained: (1) proportion of non-proliferating (G0,G1) cells as a measure of mitogen response, (2) proportion of first-cycle G2-phase cells relative to the growth fraction (G2/GF) as a measure of radiosensitivity. Of the cases tested, 94.2% could be unequivocally assigned either to the AT-negative or the AT-positive group of patients. Of the AT-positive cases, 11 were confirmed by ATM mutation analysis. Nineteen cases presented with non-conclusive results, mostly due to poor mitogen response; however, a combination of cell-cycle data with serum AFP concentrations led to the exclusion of AT in all but two of the uncertain cases. Substitution of ionizing radiation by the radiomimetic bleomycin was additionally tested in a small series of patients. We conclude that cell-cycle testing complemented by serum AFP measurements fulfills the criteria as a rapid and economical screening procedure for the differential diagnosis of juvenile ataxias.     

Nasal air temperature and airflow during respiration in numerical simulation based on multislice computed tomography scan

BACKGROUND: Adequate nasal air-conditioning is of greatest importance. Because detailed processes of nasal air-conditioning still are not completely understood, numerical simulations of intranasal temperature distribution and airflow patterns during inspiration and expiration were performed. METHODS: A three-dimensional model of the human nose based on computed tomography scans was reconstructed. A computational fluid dynamics application was used displaying temperature and airflow during respiration based on time-dependent boundary conditions. RESULTS: Absolute air temperature and velocity values vary depending on detection site and time of detection. Areas of low velocities and turbulence show distinct changes in air temperature. The turbinate areas prove to be the main regions for heat exchange. The numerical results showed excellent comparability to our in vivo measurements. CONCLUSION: Numerical simulation of temperature and airflow based on computational fluid dynamics is feasible providing entirely novel information and an insight into air-conditioning of the human nose.     

Functional results after laparoscopic rectopexy for rectal prolapse

We investigated the functional results after laparoscopic rectopexy for rectal prolapse in 29 patients at least 12 months postoperatively. Twenty patients were evaluated completely pre- and postoperatively (median 22 months postoperatively, range 12 to 54 months). Six patients were interviewed by telephone, two patients were lost to follow-up, and one patient died of causes unrelated to rectal prolapse. Patients underwent a proctologic examination, anoscopy, rigid sigmoidoscopy, fluoroscopic defecography, and anorectal manometry pre- and postoperatively, and an additional standardized interview postoperatively. Anorectal manometry showed a significant increase in maximum anal resting and squeeze pressures postoperatively (resting pressure 72 ±8 vs. 95 ±13 mm Hg, pre- vs. postoperatively; P = 0.046; squeeze pressure 105 ±17 vs. 142 ±19 mm Hg, pre- vs. postoperatively; P = 0.035), and continence improved postoperatively (Wexner incontinence score 6.0 ±1.0 vs. 3.9 ± 0.8 pre- vs. postoperatively, P = 0.02). Twenty (77%) of 26 patients were satisfied with the operative result, but functional morbidity was observed in four patients, with two patients complaining of severe evacuation problems. Rectal prolapse recurred in one patient 42 months postoperatively (recurrence rate 1 [3.8%] of 26 patients). Functional results were very similar to those obtained after open rectopexy, with symptoms of prolapse and incontinence improved in the great majority of patients. Presented at the Fortieth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Fla., May 16–19, 1999.     

Acute effects of alcohol on divided and covert attention in men

RATIONALE: While several studies identified divided attention to be sensitive to alcohol effects, the impact of alcohol on covert visual attention is still not clear, despite the latter's important role in perception. OBJECTIVES: The study tests the effect of acute moderate doses of alcohol on divided and covert attention in right-handed, male volunteers. METHODS: The design of the study involved a double-blind trial with an alcohol and a placebo condition; measurements were taken before and after an oral dose of 0.6 g/kg alcohol versus placebo. In the divided-attention task, simultaneous visuo-spatial and auditory stimulation was applied. In a test of covert attention, subjects had to shift their attentional focus according to a central cue, from one location in the visual field to another. RESULTS: Under the divided-attention condition, reaction times were significantly prolonged after alcohol ingestion compared to placebo. Covert attention pre-post change was also significantly different between the alcohol and placebo groups. There is a reduction of false-cueing disturbance for left-appearing stimuli under moderate alcohol but an increase of disturbance for rightward stimuli, i.e. we found a lateralised pattern of reaction for spatial orienting. In the placebo group, no significant differences in right-left performance were obtained. CONCLUSION: The results suggest that sensory-attentional mechanisms play a key role in altered visual perceptual performance after alcohol ingestion. Furthermore, differences between the right and left visual field in the cued target-detection task indicate that alcohol exerts an influence on right-hemispheric attentional priming.     

Gc-globulin concentrations and C5 haplotype-tagging polymorphisms contribute to variations in serum activity of complement factor C5

OBJECTIVES: To investigate the role of Gc-globulin and C5 gene variants as co-factors in the regulation of profibrogenic C5 serum activities. DESIGN: Retrospective clinical investigation with 100 healthy probands. Genomic DNA was isolated from whole blood and examined for the human C5 htSNPs rs17611 and rs2300929. Actin-free Gc-globulin-, total Gc-globulin- and total C5-concentrations in serum were measured using ELISA assays; C5 activities in serum were determined using radial immunodiffusion. RESULTS: C5 serum concentrations were significantly elevated in individuals carrying at least one profibrogenic allele of the C5 htSNP rs17611, but no association between C5 htSNPs and C5 serum activities was detected, albeit C5 activities correlated positively with C5 concentrations in serum. However, C5 activities were also positively correlated with total and actin-free Gc-globulin concentrations. CONCLUSION: Our findings indicate that C5 gene variants and Gc-globulin levels co-define the proinflammatory and profibrogenic effects of C5 in patients at-risk for progression of liver fibrosis.